This proposal details the comprehensive 5-year training program in patient-oriented research for the CANDIDATE, Sun H. Kim M.D., an instructor (pending) in the Division of Endocrinology at Stanford University School of Medicine. Her main research interest is in understanding the relationship between schizophrenia and type 2 diabetes, a highly prevalent disorder in the schizophrenia population. During the Career Development Award, her goals will be to obtain didactic, clinical, and experimental training in diabetes and psychiatry research, with a focus on building expertise to work with patients with schizophrenia. Stanford provides a rich ENVIRONMENT with supportive faculty in endocrinology and psychiatry to assist with the candidate's goals. Dr. Gerald Reaven, an internationally-recognized expert in diabetes research, will mentor the candidate, along with Drs. Alan Schatzberg and Douglas Levinson, both senior, distinguished researchers in mental health. The RESEARCH proposal will evaluate the role of a widely-used antipsychotic medication-olanzapine-in mediating the association between schizophrenia and diabetes by focusing on its effect on pancreatic -3-cell function, the requisite defect in diabetes. SPECIFIC AIMS will directly evaluate: 1) whether olanzapine treatment impairs glucose-stimulated insulin secretion (GS-ISR), one of the fundamental functions of the pancreas, in nondiabetic, insulin-resistant patients with schizophrenia (who are most vulnerable to develop diabetes) compared with patients treated with other atypical antipsychotic medications with less diabetes risk (risperidone, quetiapine, and ziprasidone); 2) whether olanzapine attenuates free-fatty-acid-induced GS-ISR, another important pancreatic function; and 3) whether olanzapine increases peripheral insulin resistance in overweight patients with schizophrenia. Unlike previous studies, rigorous methods to measure insulin resistance (Insulin Suppression Test) and pancreatic (3-cell function (Graded-glucose Infusion Test) will be used. The conclusions of this proposal will fill an important gap in understanding olanzapine-associated diabetes, a growing concern in mental health, and will elucidate how olanzapine (one of the top-ten selling medications in the United States) will be used in the future. Also, the conclusions will guide prevention and intervention efforts to decrease type 2 diabetes, a major cause of morbidity and mortality, in the schizophrenia population. [unreadable] [unreadable] [unreadable]